Most breast tumors contain estrogen receptors (ER) that regulate tumor cell growth and mediate the action of estrogen antagonists such as tamoxifen. Not all breast cancers, however, respond to hormone therapy. Therefore, it is important to have effective prognostic tools that will identify those patients most likely to be hormone responders, so that they can be treated with this well tolerated therapy, whereas those unlikely to respond can promptly begin regimens of radiation of chemotherapy. The presence of ER in most breast tumors provides a mechanism for selective localization of estrogens, which if labeled with suitable radionuclides, could be used for diagnostic imaging or radiotherapy or breast tumors. During past periods of support on this project, we have developed a series of estrogens labeled with fluorine-18 and carbon-11, some of which are effective agents of imaging estrogen receptor positive (ER+) tumors. Other investigators have developed other adiohalogenated estrogens for ER-mediated radiotherapy. Other investigators have developed other radiohalogenated estrogens for ER-mediated radiotherapy. Also, recent investigations have revealed that another estrogen receptor subtype, ERbeta, is present in some target tissues, including breast tissue and tumors. We have three goals of the next phase of this project: (1) We intend to develop ER ligands for breast tumor imaging that are labeled with the readily available radionuclide, technetium-99m, as well as its rhenium congener. To accomplish this, we will investigate novel aspects of technetium organometallic chemistry through the application of three new methods for the preparation of cyclopentadienyl tricarbonyl technetium and related systems. These functionalities will be incorporated are pendant and integral groups into steroidal and non-steroidal ER ligands. (2) Based on emerging differences in the structure-binding affinity relationships for ERalpha and ERbeta ligands, derived in part from our investigations, we will prepare ligands selective for these receptors and develop them as tumor imaging agents. (3) We will utilize several radionuclides (iodine-123, and 124 and bromine-76, 77, the later three available to use through a collaboration to prepare ER ligands for radiotherapy,, and we will have these tested in appropriate animal tumor model systems. These investigations should lead to substantial advances in the availability of diagnostic imaging gents for ER+ tumors and ER subtype- selective imaging agents, to the evaluation in vivo of radiotherapeutic ER ligands.